Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

Medipally, Ajay; Xiao, Min; Rovin, Brad H.; Satoskar, Anjali A.; Ivanov, Iouri; Qaisar, Shahzeb; Brodsky, Sergey V.

doi:10.14814/phy2.14697

Cited by 6 publications

(9 citation statements)

References 27 publications

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“…In fact, dabigatran is currently the most often reported cause of ARN after warfarin. 41 Therefore, the inclusion of INR levels for the diagnosis of ARN is likely to lose value in time.…”

Section: Discussionmentioning

confidence: 99%

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IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy

Trujillo

Pérez

Cavero

et al. 2022

Kidney International Reports

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“…In fact, dabigatran is currently the most often reported cause of ARN after warfarin. 41 Therefore, the inclusion of INR levels for the diagnosis of ARN is likely to lose value in time.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the proportion of warfarin-treated patients is currently decreasing in favor of DOAC. In fact, dabigatran is currently the most commonly reported cause of ARN after warfarin [41]. Therefore, the inclusion of INR levels for the diagnosis of ARN is likely to lose value over time.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy

Trujillo

Pérez

Cavero

et al. 2022

Kidney International Reports

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“…30 Similar to animal studies with VKAs, Medipally et al observed acute tubular epithelial cell injury, red blood cell casts in the tubules and an increase in blood pressure in 5/6 nephrectomy rats treated with dabigatran. 31 Additionally, the modification of the eGFR by angiotensin-converting enzyme inhibitor, enalapril, seemed not to have any effect on dabigatran-induced ARN in that study. 31 Importantly, Ryan et al observed ARN not only in 5/6 nephrectomy rats, but also in control animals receiving dabigatran in a dosedependent manner, 32 differently than in animal studies with VKAs.…”

Section: Pathogenesismentioning

confidence: 59%

“…31 Additionally, the modification of the eGFR by angiotensin-converting enzyme inhibitor, enalapril, seemed not to have any effect on dabigatran-induced ARN in that study. 31 Importantly, Ryan et al observed ARN not only in 5/6 nephrectomy rats, but also in control animals receiving dabigatran in a dosedependent manner, 32 differently than in animal studies with VKAs. Despite histopathological changes comparable to those observed in 5/6 nephrectomy rats after the administration of VKAs, the effect of a PAR-1 antagonist, SCH79797, was lesser than that of dabigatran, indicating that the inhibition of PAR-1 only partially explains the mechanism of ARN observed after this DOAC (Fig.…”

Section: Pathogenesismentioning

confidence: 59%

Anticoagulant-related nephropathy: Focus on novel agents. A review

Zakrocka¹,

Załuska²

2022

Adv Clin Exp Med

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Anticoagulant-related nephropathy (ARN) is a novel and not well-studied cause of acute kidney injury (AKI). The prevalence of ARN varies significantly between studies and is estimated at 20% in patients treated with warfarin. Patients with ARN have a significantly higher mortality risk and an increased risk of chronic kidney disease (CKD). Unexplained AKI with hematuria are clinical manifestations of ARN. In most cases, ARN is diagnosed within the first 2 months of anticoagulant therapy, but later ARN occurrence is possible. Among the studied anticoagulants, most data concern warfarin toxicity, whereas cases of ARN caused by direct oral anticoagulants (DOACs) have also been presented. Tubular obstruction by red blood cell casts or hemoglobin and iron tubular toxicity are the postulated mechanisms of ARN. On the molecular level, the inhibition of thrombin and protease-activated receptor-1 (PAR-1), leading to endothelial susceptibility to damage or abnormal protein C endothelial signaling, is suggested to contribute to ARN. Older age, impaired kidney function, hypertension, and diabetes mellitus are the main risk factors for ARN, but their significance may differ between anticoagulants. From therapeutic options, the withdrawal of the anticoagulant and the administration of its antidote, as well as corticosteroids or N-acetylcysteine, are proposed. Since the number of patients with kidney diseases on anticoagulants increases, and DOACs are starting to be more useful in this group of patients, we aim to summarize the pathogenesis, clinical picture and possible ways of treatment of DOAC-induced ARN.

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“…Limitations of our studies include that only one anticoagulant is tested. However, our previous data indicate that the short-term kidney effects of other anticoagulants (such as direct thrombin inhibitor dabigatran) are similar to those of warfarin (30)(31)(32)(33). Studies with other anticoagulant classes (such as direct thrombin inhibitors or Factor X antagonists) are warranted to investigate their effects on kidney function, but based on our data, the main effect of warfarin on the kidney fibrosis is mediated through hematuria; therefore, one may suggest that effects of other anticoagulants will be similar to those of warfarin.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hematuria Increases Chronic Kidney Injury and Epithelial–Mesenchymal Transition in 5/6 Nephrectomy Rats

et al. 2021

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Chronic kidney disease (CKD) is a common outcome of many kidney diseases. Interstitial fibrosis and tubular atrophy (IFTA) is a histologic hallmark of CKD. Hematuria is a common symptom in many human kidney diseases. Free hemoglobin may affect tubular epithelial cells by generating reactive oxygen species (ROS). Epithelial–mesenchymal transition (EMT) of the tubular epithelial cells has been shown to play an important role in the IFTA development. The aim of this study was to determine the effects of chronic hematuria on the CKD progression in 5/6 nephrectomy (5/6NE) rat model of CKD. 5/6 NE rats were treated with oral warfarin (0.5 mg/kg/day) or vehicle (control). The animals were monitored for 26 weeks, while prothrombin time (PT), serum creatinine (SCr), and hematuria were measured weekly. Staining for iron, trichrome, and EMT (vimentin, E-cadherin, smooth muscle actin) markers was performed on the remnant kidneys. ROS were detected in the kidneys by protein carbonyl assay and immunohistochemistry for heme oxygenase 1 (HMOX1), at the end of the study. Apoptosis was detected by TUNEL assay. Warfarin treatment resulted in a PT increase 1.5–2.5 times from control and an increase in hematuria and SCr. Histologically, warfarin-treated animals had more iron-positive tubular epithelial cells and increased IFTA as compared to control (42.9 ± 17% vs. 18.3 ± 2.6%). ROS were increased in the kidney in warfarin-treated rats. The number of tubules that show evidence of EMT was significantly higher in warfarin-treated 5/6NE as compared to control 5/6NE rats. The number of apoptotic tubular epithelial cells was higher in warfarin-treated 5/6 NE rats. Chronic hematuria results in increased iron-positive tubular epithelial cells, EMT, apoptosis, and more prominent IFTA in CKD rats. Our data suggest an important role of chronic hematuria in the progression of CKD.

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Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

Cited by 6 publications

References 27 publications

IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy

IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy

Anticoagulant-related nephropathy: Focus on novel agents. A review

Chronic Hematuria Increases Chronic Kidney Injury and Epithelial–Mesenchymal Transition in 5/6 Nephrectomy Rats

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